1-(3-Hydroxy-4-alkyl-phenyl)-alkylamines(-2) and the salts thereof

ABSTRACT

Compounds represented by the formula   WHEREIN R1 is a member of the group consisting of CH3, C2H5 and C3H7, and R2 in position 2, 4, 5 or 6 on the benzene nucleus is a member of the group consisting of F, Cl, Br, CH3, C2H5 and C3H7, pharmaceutical compositions containing these compounds, and the use thereof for therapeutic purposes.

States Carlsson et a1.

atent 1 1 Dec. 30, 1975 [54] l-(3-HYDROXY-4-ALKYL-PHENYL)-ALKYLAMlNES(-2) AND THE SALTS THEREOF [75] Inventors: Per Arvid EmilCarlsson, Goteborg;

Hans Rudolf Corrodi, Askim; Sven Goran Hallhagen, Molndal; Ulf KristerJunggren, Goteborg, all of Sweden [73] Assignee: Aktiebolaget Hassle,Gothenburg,

Sweden [22] Filed: June 21, 1973 [21] Appl. No.: 372,088

Related U.S. Application Data [60] Division of Ser. No. 811,662, March28, 1969, Pat. No. 3,655,737, which is a continuation of Ser. No.171,017, Aug. 11,1971, abandoned.

[30] Foreign Application Priority Data Apr. 1, 1968 Sweden 4332/68 [52]U.S. Cl 260/501.17; 260/570.8 R; 260/600;

260/612 D; 424/316; 424/330 [51] Int. Cl. C07C 87/29 [58] Field ofSearch.... 260/570.8 R, 501.17

[56] References Cited UNITED STATES PATENTS Green 260/570.8

10/1970 Keck et a1 260/50l.1 X 8/1971 Gold 260/570.8 X

OTHER PUBLICATIONS Wenner, Journal Organic Chemistry, Vol. 16, pp.457-460, (1951).

Primary ExaminerR. V. Hines Attorney, Agent, or Firm-Brumbaugh, Graves,Donohue & Raymond wherein R is a member of the group consisting of CH CH and C H and R in position 2, 4, 5 or 6 on the benzene nucleus is amember of the group consisting of F, Cl, Br, CH C 11 and C H,,pharmaceutical compositions containing these compounds, and the usethereof for therapeutic purposes.

2 Claims, No Drawings 1-(3-HYDROXY-4-ALKYL-PHENYL)- ALKYLAMINES(-2) ANDTHE SALTS THEREOF This application is a division of Ser. No. 81 1,662filed 03/28/69 and now U.S. Pat. No. 3,655,737; which is a continuationof application Ser. No. 171,017, filed Aug. 1], 1971 and now abandoned.

The present invention relates to substituted hydroxyphenyl-alkylamineshaving valuable pharmacological properties and pharmaceuticallyacceptable salts thereof. The compounds of the invention are ofparticular value as hypertensive agents and as agents for treatment ofmental illness, especially as antidepressant agents. The invention alsorelates to methods for the preparation of such compounds, compositionscontaining them and the use of such compounds for therapeutic purposes.In particular the invention relates to compounds of the formula whereinR is a member of the group consisting ofCl-1 C H and C l-1 and R inposition 2, 4, 5 or 6'0n the benzene nucleus, is a member of the groupconsisting of F, Cl, Br, CH C 11 and C l-1 Prior art compounds are3-hydroxy-4-methylnorephedrine;

Nll

HOCHCH and a-methyl-m-tyramine:

N11 CH %H CH (III) without giving rise to undesired sympathomimetic sideeffects. Surprisingly it has been found that the compounds of theinvention are able to penetrate into the brain, where they -are taken upby the noradrenergic neurons and act there as false transmitters. Thisvaluable and unexpected property contributes to the antihypertensive andantidepressant activity of the compounds.

The prior art compound II has no antihypertensive and antidepressanteffects, since it does not penetrate into the brain and displacenoradrenaline there.

The prior art compound 111 does penetrate the blood brain barrier, butshows a high sympathomimetic activity which leads to an increase inblood pressure. The increase in blood pressure caused by this sideeffect overshadows the antihypertensive effect which might be expectedfrom the ability of the compound to act as a false transmitter in thenoradrenergic neurons of the brain. Furthermore, the compound III ismore toxic than the compounds disclosed in this invention.

An additional advantage of the compounds of this invention over thementioned prior art compounds is that the substances disclosed hereinare able to liberate 5-hydroxytryptamine in the brain. This propertycontributes mainly to the antidepressant activity of the compounds. Noneof the mentioned prior art compounds shows this effect.

The compounds of the invention may be prepared by I known methods suchas A. replacing Z with H in a compound of the formula HCH wherein R andR have the meanings specified above and wherein Z is a member of thegroup consisting of alkyl and acyl protecting groups, by means of astrong acid such as HBr to the formation of a compound of the formula 1;

B. replacing Z with H by catalytical hydrogenation of a compound of theformula 11 on on 1 III 3 4 wherein R has the meaning specified above; Ris a member of the group consisting of CH;,, C H and Sill CNO C H andwherein Z is a member of the group conl sisting of aralkyl protectinggroups, such as benzyl; to R the formation of a compound of the formulaI; 5 VI C. reducing a compound of the formula OH i 1 wherein R and Rhave the meanings specified above,

to the formation of a compound of the formula I; IV [5 whereafter thecompound of the formula I thus obtained if necessary is transformed intoa therapeutically R OH acceptable salt by reaction with the appropriateacid.

Z is preferably a methyl group, and Z is preferably a benzyl group. Zmay be split off by strong acids such as HBr, and

Z may be split off by hydrogenolysis.

The reaction way D is applicable only in those cases wherein R and Rhave the meanings specified above, when the substituent R in thecompound of the forin the presence of HCOOH according to Leuckart to l Ii CH C l-{ r C H catal ti l removal the formation of a COmPOLmd 0f theformula I; of araliphatic protecting groups is not applicable when D.reducing a compound f t fOrmula the substituent R is F, Cl or Br. When Ris CH;;,

C H or C H all the outlined reaction ways can be used, and catalyticalremoval of an araliphatic protecting group is possible.

The reduction of the compound of the formula V is 2 preferably carriedout by catalytical hydrogenation. HOCHCH The reduction of the compoundof the formula V] is 1 preferably carried out by means of a complexmetal hydride such as lithium aluminium hydride.

, V 3 5 Starting materials for the processes described above H may beprepared in any desired way. Some of the possi- R ble ways forpreparation of starting materials used in the methods A, B, C and Eabove are outlined in the following reaction schemes, which also serveas further illustrations of the various methods of preparation asdescribed above. The substituents R, R R used in the wherein R has themeaning specified above and reaction formulas have the meanings givenabove, Z is wherein R is a member of the group consisting of hydrogen orthe radical Z, and Z is hydrogen or the CH C H and C H to the formationof a comradical Z pound of the formula I; Starting materials for thereaction way D may be E. reducing a compound of the formula prepared bymethods well known per se.

Method A. CH0 CH=FNO Hzcmmfl 1 2 k 4 1 R R CH NO L1All-l 023 I 0Z3 2 0Z3R R R r l-LCl-l Method B:

CHO

l 1 2 R CH2NO2 4 s Z R3 02 3 T NH l CH CH 2 HzCllH l l (Leuckortreaction) H /Pd 4 OZ OH R R Method C:

CHO cl-tzfimo CH fo l l l R CH NO Fe HCl HBr 3 3 a R oz R R 02 'T 2 l:oCH2C\H \R l v HCOOH (Leuckcrt l reaction) 2 OH R2 H R HCQNH2 Method E:NH

CHZCNO 1 2 CH CH R L LiAlH 4 OH 2 R OH The compounds of the inventionexist in the form of 60 regeneration of the amine after the usualseparation of optically active isomers, which may be isolated in anyprincipially known way for resolution of an amine, and it is understoodthat such a manner will be included within the scope of this invention.

The racemate obtained at the above reactions can be resolved into theenantiomeres by converting the free base into a salt or an amide of anoptically active acid such as tartaric acid or any other opticallyactive acid capable of forming crystalline salts with the amine, and

the diastereomeric mixture thus obtained.

It will also be understood that the compounds of the present inventionmay be used either as a purified isome'r which is biologically active orin the form of the mixed isomeric product obtained as a naturalconsequence of the reaction sequences described above, or any otherreaction sequence for the preparation of the compounds which results ina mixed isomeric product containing the biologically active isomer orisomers.

The new compounds according to the invention may be administered in theform of salts with physiologically acceptable acids. Suitable acidswhich may be used are, for example, hydrochloric, hydrobromic,sulphuric, fumaric, citric, tartaric, maleic or succinic acid.

The invention further provides pharmaceutical compositions comprising asactive ingredient at least one of the compounds according to theinvention in association with a pharmaceutical carrier. Suchcompositions may be designed for oral, rectal or parenteraladministration.

To produce pharmaceutical preparations in the form of dosage unit fororal application containing a compound of the invention in the form ofthe free base, or a pharmaceutically acceptable salt thereof, the activeingredient may be mixed with a solid, pulverized carrier, for examplelactose, saccharose, sorbitol, mannitol, a starch such as potato starch,corn starch, maize starch or amylopectin, a cellulose derivative orgelatin, and also may include lubricants such as magnesium or calciumstearate or a Carbowax or other polyethylene glycol waxes and compressedto form tablets or centres for dragees. If dragees are required, thecentres may be coated, for example with concentrated sugar solutionswhich may contain gum arabic, talc and/or titanium dioxide, oralternatively with a lacquer dissolved in easily volatile organicsolvents or mixtures of organic solvents. Dyestuffs can be added tothese coatings. For the preparation of soft gelatin capsules(pearl-shaped closed capsules) consisting of gelatin and, for example,glycerol, or similar closed capsules, the active substance may beadmixed with a Carbowax. Hard gelatin capsules may contain granulates ofthe active substance with solid, pulverized carriers such aslactose,saccharose, sorbitol, mannitol, starches (for example potato starch,corn starch or amylopectin), cellulose derivatives or gelatin, and mayalso include magnesium stearate or stearic acid. Dosage units for rectalapplication may be in the form of suppositories comprising the activesubstance in admixture with a neutral fatty base, or gelatin rectalcapsules comprising the active substance in admixture with a Carbowax orother polyethylene glycol waxes. Each dosage unit preferably contains lto 200 mg of active ingredient.

Liquid preparations for oral application may be in the form of syrups,suspensions or emulsions, for example containing from about 0.1 to 20%by weight of active substance and also, if desired, such adjuvants asstabilizing agents, suspending agents, dispersing agents, flavouringagents and/or sweetening agents.

Liquid preparations for rectal administration may be in the form ofaqueous solutions containing from about 0.1 to 2% by weight of activesubstance and also, if desired, stabilizing agents and/or buffersubstances.

For parenteral application by injection the carrier may be a sterile,parenterally acceptable liquid e.g. pyrogen-free water or an aqueoussolution of polyvinylpyrrolidone, or a parenterally acceptable oil, e.g.arachis oil, and optionally stabilizing agents and/or buffer substances.Dosage units of the solution may advantageously be enclosed in ampoules.

When given by oral or rectal administration, the compounds of theinvention such as l-(m-hydroxy-pmetylphenyl)-butylamine (-2) and1-(m-hydroxy)-pmethylphenyl-propylamine (-2), may be given in widelyvarying dosages from, for example, 20 mg/day to l g/day, but dosages of50-500 mg/day will ordinarily be given, amounts between 100 and 300mg/day being usually preferred. When given by i.v. administration,dosages of about 5-100 mg/day, preferably about 5O mg/day may be used.

The invention is further illustrated by the following 7 Examples.

EXAMPLE 1 Preparation of Starting Material a. Preparation of1-(m-methoxy-p-methyl-phenyl)-2- nitrol -propene 28.9 g ofm-methoxy-p-methylbenzaldehyde was dissolved in ml of toluene andrefluxed with 46.8 g of nitroethane, 1.5 ml of acetic acid, 1.5 ml ofn-butylamine and 0.15 g of p-toluenesulfonic acid until the theoreticalamount of water was split off. The solution was evaporated and theresidue was purified by recrystallisation from ethanol-water.

The compounds specified in the following Table 1 were obtained in ananalogous manner. R and R have the significance given above, and Z isused to designate the protecting group used in the synthesis.

b. Preparation of m-methoxy-p-methyl-phenvlacetone To a solution of 0.8mole of l-(m-methoxy-p-methylphenyl)-2-nitro-l-propene in 300 ml oftoluene and 875 ml of water was added 326 g of iron powder and 3.3 g offerric chloride hexahydrate. The mixture was stirred and heated to C.292 ml of cone. hydrochloric acid was added at such a rate that refluxwas maintained. After addition of the hydrochloric acid, the mixture wasstirred and refluxed for one half hour, and thereafter steam-distilled.The distillate was extracted with ether, and the organic layer washedtwice with a 3 per cent sodium bisulphite solution, then water, driedover anhydrous magnesium sulphate and evaporated. The remainder was pureenough for the next step. c. Preparation ofl-(m-methoxy-p-methyl-phenyl)- propylamine (-2) 0.044 mole of thesubstituted Z-phenylpropanone, 13.5 g of freshly distilled formamide and2.5 g of formic acid was refluxed with stirring during 5 hours. Aftercooling 50 ml of water and 50 ml of hydrochloric acid was added and themixture refluxed for 5 hours. After alkalisation with 30% NaOH theproduct was taken up in ether. The organic layer was dried andevaporated.

d. Preparation of l-(m-methoxy-p-methylphenyl)- propylamine-Z 67.1 g ofl-(m-methoxy-p-methylphenyl)-2-nitro-lpropene in 200 ml of dry ether wasadded to a stirred mixture of 32 g of LiAlH in 1000 ml of dry ether at.

such a rate that the solvent refluxed gently without external heating.The mixture was stirred and heated for 2 hours. 20 ml of ethyl-acetatewas then added carefully with vigorous stirring, followed by 40 ml ofwater. The mixture was filtered and the ethereal solution was shakenwith 2-N hydrochloric acid. The amine was obtained upon alkalisation ofthe acidic solution and ether extraction. The product could be usedwithout further purification in the subsequent step. The compoundsspecified in Table 2 were prepared by the same method. R and R have thesignificance given above, and Z is used to designate the protectinggroup used.

Table 2 R R 2 Yield c11 4-c11 c11 68 CH. 5-c11 c11 40 CH 6-011 C11. 75 c11 4CH3 ca. 87 C 11. 4-c1-1 C11 30 c11 4 c1 CH;, 55

EXAMPLE 2 Preparation of 1-( m-hydroxy-p-methylphenyl )-propylamine-2 a.39.3 g of 1-(m-methoxy-p-methylphenyl)-propylamine-(2) in 300 ml ofconcentrated hydrobromic acid (d=1.49) was refluxed for 3 hours. Thesolution was then evaporated to dryness and dissolved in water. Thewater solution was made slightly alkaline with ammonia and theprecipitate recrystallized from di-isopropylether.

In an analogous way the following substances were prepared. R and R havethe significance given above.

Table 3 R R M.p. c

CH 4CH3 134 CH 5CH,, 10o CH 6C1-l;, 131 c 11 4Cl-l 107 C 11 4-CH3 1 17CH3 4-Cl 137 b. 1.81 g of m-hydroxy-p-methyl-norephedrine was dissolvedin 20 ml of 1N hydrochloric acid and hydrogenated with Pd/C as catalystat 50. After 5 hours 250 ml of H had been taken up and the desoxybasewas isolated by alkalisation of the filtered solution. Afterrecrystallization from di-isopropylether the melting point was found tobe 134C. The substance was identical with the one obtained in example2a.

EXAMPLE 3 EXAMPLE 4 Tablets Each tablet contains: Active substance 50.0mg Maize starch -continued Lactose 160.0 mg Gelatin 1.5 mg Talc 12.0 mgMagnesium stearate 1.5 mg 250.0 mg

EXAMPLE 5 Suppositories Each suppository contains: Active substance 50.0mg Ascorbyl palmitate 1.0 mg Suppository base (Imhausen H) ad 2000.0 mg

EXAMPLE 6 Syrup Active substance 0.500 g Liquid glucose 30.0 g Sucrose50.0 g Ascorbic acid 0.1 g Sodium pyrosulfite 0.01 g Disodium edetate0.01 g Orange essence 0.025 g Certified colour 0.015 g Purified water ad100.0 g

EXAMPLE 7 Injection Solution Active substance 0.100 mg Sodiumpyrosulfite 0.500 mg Disodium edetate 0.100 mg Sodium chloride 8.500 mgSterile water for injection ad mg EXAMPLE 8 Solution for RectalAdministration (Rectal Vials) Active substance 20.0 mg Sodiumpyrosulfite 1.5 mg Disodium edetate 0.3 mg Sterile water ad 3.0 ml

EXAMPLE 9 Drops Active substance 2.00 g Ascorbic acid 1.00 g Sodiumpyrosulfite 0.10 g Disodium edetate 0.10 g Liquid glucose 50.00 gAbsolute alcohol 10.00 g Purified water ad 100.0 ml

EXAMPLE 10 Tablets Active substance (50 g), lactose (100 g), Calciumcitrate (50 g), and starch (50 g) are mixed together and granulatedusing a 10% agueous gelatin solution. The granules are passed through a20-mesh sieve, mixed with magnesium stearate (1.5 g) and talc (5 g), andthen tabletted using a 9 mm punch.

PHARMACOLOGICAL TESTS I. Effect as Releasers and Displacers ofNoradrenaline in the Mouse Brain 111. Antihypertensive Effect When1(m-hydroxy-p-methylphenyl)-propylamine- 2 was given as a solution inthe drinking water to re- The substances were given intraperitoneally tomice hypertensive rats in doses of 5 l0 mg/kg/day their (male, NMRI,b.w. of 1822 g) in a dosage of 30 blood Pressure (170400 mmHg).decreased mg/kg. 6 animals per group were used. The noradrena- 1004 g ma few days and remamed there 9 line in the brains was determinedfluorometrically acthe admlmstranon of the l was 9: The pnor cording toBertler Carlsson and Rosengren Acta art compounds II and 111 did notreact similarly when phySiOL Scand' 44 273 (1958) 1 2 4 and 8 hoursafter 10 administered in the same dosage; compound 11 does not theadministration. The valves are given in percents of 1 blQOd Pressure andCompound In Causes an 1mnormal values (450 i 9 ng/g) tial increase inblood pressure to 190-210 mm Hg due Table 4 R R2 Amount of noradrenalinein the brain. sympathomimetic Percent of normal values after effect(piloerection salivation, exoftall 2 4 8 hrs mos) CH 4CH3 60.6 48.6 37.54811 CH3 4C2H5 75.8 68.3 60.5 6815 C l-l 4CH3 91.0 85.4 80.0 92.5 C21154-CH3 90.1 87.4 88.1 96.3 CH3 5CH3 70.8 51.4 68.3 87.2 CH3 6CH;, 74.559.8 67.8 99.0 Com- 11 97.2 99.0 102.5 103.7 llpound Com- 111 72.5 54.253.1 61.3 -lll1- pound This test Shows to its sympathomimetic effect,whereafter the blood a. that the prior art compound II,3-hydroxy-4-methpress ure decreaseshmoderately h yl-norephedrine, doesnot penetrate into the brain and Thls test shows t at Compounds lpenetrate displace noradrenaline which would result in a into the brainand cause liberation and displacement of Crease of noradrenaline in thebrain noradrenaline there have antihypertensive activity. The

b. that the prior art compound Ill, a-methyl-m-tyracompound has an l f lacuon mine, has an unwanted high sympathomimetic effect Whlch 1S masks?by the y lP l q of leading to excessive Signs of piloerectionsalivation, substance leading to an initial undesirable increase inexoftalmos blood pressure.

0. that the substances disclosed in this invention pen- Eff t asReieasers and Dispiacers f etrate into the brain and cause release ofnoradrenaline 5 Hydroxytryptamine in the Mouse Brain throughdisplacement (expressed as a decrease in nor- 4O Substances according tothe invention were given adrenaline) without causing disturbingsympathomimetic effects.

11. Toxicity The intraperitoneal and the peroral toxicity was determinedas LD in mice.

4 hours after the administration.

This test shows that the compounds disclosed in this invention have alow intraperitoneal and oral toxicity compared with the prior artcompounds 11 and 111.

The values are given in percents of normal values (460 14 ng/g).

Table 6 R R Dose mg/kg Amount of S-hydroxytryptamine after 4 hours;percent of normal values CH 4CH 82.2 CH 4C H 50 62.2 C 11 4CH 51.0 CH,5-CH 100 89.1 CH; 6--Cl-l 100 87.3 C H 4CH 100 85.4

Table 6-continued R R Dose mg/kg Amount of S-hydrox tryptamine after 4hours; percent normal values Compound 11 50 103.3

Compound lll 50 119.1

l. l-(3-hydroxy-4-ethyl-phenyl)-propylamine(-2 or their opticalantipodes) or therapeutically acceptable salts thereof.

2. l-(3-hydroxy-4-methyl-phenyl)-butylamine(-2) or their opticalantipodes or therapeutically acceptable salts thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. I 3, 929,871

DATED I December 30, 1975 rNyg o rs) Per Arvid Emil Carlsson et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

First Page, Item [60], "Division of Ser. No. 811,662, March 28, 1969,Pat. No. 3,655,737,- which is a continuation of Ser. No. 171,017, Aug.11, 1971, abandoned." should read -Continuation of Ser. No. 171,017,Aug. 11, 1971, abandoned, which is a division of Ser. No. 811,662, March28, 1969, Pat. No. 3,655,737.-; Col. 1, lines 3-6, "This application isa division of Ser. No. 811,662 filed 03/28/69 and now U.S. Pat. No.

3,655,737; which is a continuation of application Ser. No.

171,017, filed Aug. 11, 1971 and now abandoned." should read --Thisapplication is a continuation of application Ser. No. 171,017, filedAug. 11, 1971, abandoned, which is a division of U.S. application Ser.No. 811,662, filed March 28, 1969, and now U.S. Pat. No. 3,655,737.-;Col. 14, line 10, after "(2 insert and Col. 14, line 11, after"antipodes" delete Signed and Scaled this v Sixth Day of July 1976 sue Artesl:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner of Parentsand Trademarks UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO. 3, 929,871

DATED December 30, 1975 0 (5) Per Arvid Emil Carlsson et a1.

It is certified that error appears in the aboveidentitied patent andthat said Letters Patent are hereby corrected as shown below:

First Page, Item 0 "Division of Ser. No. 811,662, March 28, 1969, Pat.No. 3,655,737, which is a continuation of Ser. No. 171,017, Aug. 11,1971, abandoned." should read --Continuation of Ser. No. 171,017, Aug.11, 1971, abandoned, which is a division of Ser. No. 811,662, March 28,1969, Pat. No. 3,655,737.-; Col. 1, lines 3-6, "This application is adivision of Ser. No. 811,662 filed 03/28/69 and now U.S. Pat. No.3,655,737; which is a continuation of application Ser. No. 171,017,filed Aug. 11, 1971 and now abandoned." should read -This application isa continuation of application Ser. No. 171,017, filed Aug. 11, 1971,abandoned, which is a division of U.S. application Ser. No. 811,662,filed March 28, 1969,

and now U.S. Pat. No. 3,655,737.--; Col. 14, line 10, after (-2" insertand Col. 14, line 11, after "antipodes" delete Signed and Scaled thisSixth Day of July 1976 sen Arrest:

RUTH C. MASON C. MARSHALL DANN Commissioner of Parents and TrademarksArresting Officer

1. 1-3-HYDROXY-4-ETHYL-PHENYL)-PROPYLAMINE(-2 OR THEIR OPTICALANTIPODES) OR THERPEUTICALLY ACCEPTABLE SALTS THEREOF. 2.1=(3-HYDROXY-4-METHYL-PHENYL)-BUTYLAMINE(-2) OR THEIR OPTICAL ANTIPODESOR THERAPEUTICALLY ACCEPTABLE SALTS THEREOF.